Esters of inorganic acids and process of making same



Patented Aug. 7, 1945 2,381,073 I ss'rsns or'moacamc ACIDS AND raocsss or MAKING same:

Karl Miescher, Riehen, and Charles Meystre,

Basel, Switzerland, asslgnors to Cilia Pharmaceutical Products Inc., Summit, N. 1., a corporation of New Jersey No Drawing. Application June 15, 1942, Serial No. 447,150. In Switzerland July 21, 1941 6 Claims.

It has been found that esters of inorganic acids can be obtained if poly-hydroxy compounds having the action of a sex hormone, which have been partially esterifled or etherifled, are treated with esterifying agents which are capable of ingroups, be converted into salts.

yl-ether groups.

some cases diluents may be' conveniently used.'

Schotten-Baizmann's method, for example, can also be used.

Finally, the mixed esters containing organic' and inorganic acids-or the ester-ethers of the poly-hydroiw compoundwith the action of a sex hormone'may be partially split. Hydrolyzing agents, both acid and alkaline, are most suitable iorthis purpose. Partial splitting can also radicals can be removed conveniently by using reducing agents. In our experiments the surprising observation was made that the inorganic acid radicals, in general, are much more difli- 5 cult to remove than the organic acid or the ether troducing inorganic acid radicals. The mixed radicals so that partial elimination of the latter esters of organic and inorganic acids or etheris very easily possible.

esters obtained may then be partially split and Esters prepared by this process which still the esters produced, which still contain free acid possess free acid groups can finally be convert- 10 ed if desired into salts. In this way salts which Suitable starting materials for the new procare only slightly soluble in water and others ess are, in general, saturated or unsaturated which are easily soluble may be obtained. The poly-hydroxy compounds which have the action latter have a special therapeutic significance beof a sex hormone and are partially esterifled with cause aqueous solutions of these salts can be inorganic acids or etherifled with alcohols'or phel5 Jected. For the manufacture of the salts, inorthey may be of any steric configuration. ganic or organic substances can be used which As examples may be given: estradiol, estriol, form salts-with acids. e. g. hydroxides or 'carandrostanediol, androstenediol, poly-hydroxy bonates of the alkalis, alkaline earths and amcompounds of the dialkyl-stilbene series, of the monia, or amines such as diethylamine, ethyldiphenyl-dialkyl ethane series or the diphenyl- 20 enediamine. mono-, diand triethanolamine, dialkylene ethane series. The acid radicals may piperidine. etc. be of aliphatic, aromatic, alicyclic or hetero- The new process has the advantage over the cyclic nature or, for example, radicals of sulprocesses which utilize direct partial esterificaionic acids. Suitable ether radicals are, for extion with inorganic esterifying agents or partial ample, alkyl-, benzyl-, triarylmethylandphen- 2 saponiflcation of poly-esters of inorganic acids These mono-esters or monoand also over the reduction of inorganic esters ethers may be prepared by an already known of hydroxy-ketones, in giving better yields;- it method, e. g. by partial saponiflcation of 'polyleads, in contrast to the last named process, to esters, polyethers or ether-esters; by partial sterically uniform products. esteriflcation or etheriflcation of free. poly-hy- The following examples illustrate the in'vendroxy compounds having the action of a sex tion, but are not to be regarded as limiting it in hormone or by reduction of esterified or etheriany way, the parts being by weight. fled hydroxy-ketones having the action of a sex Example 1 In the first stage of the process, the starting. 35 1.7 parts of phosphorus oxychloride are dismaterials are treated with esterifying agents, solved in 10 parts of pyridine at -10 C. To suitable for introducing inorganic acid radicals, this solution is added at -10 C. asolution of e. g. with the corresponding inorganic acid 'it- 1.9 parts of stradi -iin nz a in 0 self or its halides, anhydride or esters, e. g. phosparts of py d Whifihv has 9-180 been cooled phorus oxychloride, phosphorus pentachloride, to l0 C, The reaction mixture is allowed to phosphorus pentoxide, meta-phosphoric acid, stand for one hour at 10'C., moisture being chloro-sulionic acid or boric acid. The'ester is excluded: pyridine hy hl ri e is r l y prepared by a known method. C0ndensing deposited. The mixture is slowly poured into agents such. as pyridine. quinoline etc. and in ice. stirrin continuously. and ly a saturated solution of sodium bicarbonate added until the mixture has an alkaline reaction to litmus. The whole is shaken up several times'with ether to remove the pyridine and traces of unchanged starting material; The aqueous solution. which 'be carried out by utilizing'a re-esteriiying 1 contains the estradiol-3-benzoate-17-primarymono-(phosphate. is made acid to congo with hydrochloric acid, then 5 per cent. of its volume of concentrated hydrochloric acid are added, and the 'Whole is allowed to stand overnight at room temperature for the-benzoic acid radical in the 2 assnovs N/lO caustic soda up to the end-point with methyl-orange, and then with phenolphthalein, already a practically pure primary l'l-monophosphoric acid ester of estradiol. It can be precipitated from an aqueous solution of alkali carbonates or alkali hydroxides by the addition of hydrochloric acid. The product, after recrystallization, melts at 216-217 C.

Instead of estradiol-S-monobenzoate, another estradiol-s-mono-ester can be used, c. g. the acetate, proplonate, hexahydrobenzoate or toluenesulionate or an estradiol-li-monc-ether such as. the triphenylmethyl-ether or the benzyl-ether. Ii the last named is used, reducing agents e. g. bisulflte salts may be used instead of acid agents for the subsequent splitting.

The primary i'l-mono-phosphoric acid ester obtained may subsequently be converted into any salt. I

For the preparation of the mono-sodium salt,

for instance, the following method is adopted;

to 1 part or the ester mentioned, a slight excess (above the calculated quantity) of sodium bicarbonate solution is added and the mixture warmed until solution is complete. The filtered solution is cooled, the precipitated mono-sodium salt of the primary l'l-monophosphoric acid ester of estradiol sucked oil and washed with a little cold water.

The ethanol amine salt can be prepared, for example, by dissolving one part oi the l'l-monophosphoric 'acid ester in hot alcohol and adding somewhat more than the calculated quantity of ethanol amine. The white crystals, which are almost insoluble in alcohol are filtered oil with suction and washed with ethanol. an unsharp melting point at PIS-205 C.

Solutions of the tri-ethanol-amine salt can be prepared, for example, by shaking up one part of the l'l-monc-phosphorlc acid ester with a solution oi somewhat more than the calculated quantity of tri-ethanol-amine in water, when the ester easily soes into solution. The alkaline solution can be neutralized by saturating, for instance, with carbon dioxide.

Example 2 1.7 parts of phosphorus oxychloride are dissolved in 10 parts of pyridine at 10 C. To this solution is added a solution of 2 parts estradiol-.

- recrystallization from a mixture oi acetone-and ether, shows an unsharp melting point at 185- 187 C., after previous sintering.

Instead of the acid hydrolysis described in Example 1', alkaline agents may also be used for the partial saponiilcation of the radicalin the l'l position. For example, the propionic acidphosphoric acid-diester is dissolved in 2N-soda solution and the solution heated for one hour at so-9oc. The cooled solution is then acidified They show '45 G scribed in Example 1 to the primary 3-monophosphoric acid ester of estradiol.

In a similar way other 3- or 17-mono-esters of inorganic acids of estradiol can be prepared e. g. secondary phosphates, primary or secondary sulphates etc.

The phosphoric acid ester described can be converted into its mono-sodium salt in the same way as the l'l-ester. Any other salts e. g. dialkali salts can also be prepared. The calcium salt may be obtained, for example, by suspending 'one part of the phosphoric acid'ester ,in 20 parts of water and shaking with a solution of 3 parts calcium acetate in 10 parts water. Instead of salts with inorganic bases, salts with organic bases such as mono-ethanol amine, di-ethanol-amine or triethanol-amine, pyridine, quinoline, piperidine or trimethylamine can also be prepared.

Example 3 2 parts M-androstene-3z17-diol-8-monoacetate are reacted with phosphorus oxychloride in pyridine as described in Example 2. The 3.-acetate-l'l-primary-mono-phospbate obtained is partially hydroyzed with soda solution and the primary. l'l-mono-phosphoric acid ester of androstenediol thin obtained. The latter may be converted by a known method, using oxidizing or dehydrogenating' agents, into the primary testosterone-ll-phosphoric acid ester or its salts.

The sulfates or borates, for example, of androstenediol, or their salts can be obtained in a similar way. It is possible to start from S-monctriphenyl-methylether, ior example, instead of from androstene-diol-a-m'onoacetate, carrying out the partial hydrolysation with acid agents.

It instead or the S-mono-derivative's oi androstenediol the corresponding l7-mono-derivatives are used, the s-monors or androstene-diol containing organic acid cals or their salts are obtained.

Example 4 1.7 parts chloro-sulronic acid are dissolved at -10' C. in 10 parts dimethylaniline. To this solution is added a solution of 2 parts diethylstilboestrol monobensoate or melting point 140- 141 C. (prepared tor example. by partial esteriflcation-oi diethyl stilboestrol with benscic anhydride in boiling py dine) in 10 parts dimethylaniline, which has also been previously cooled. Alter standing for 1 hour, the reaction mixture is slowly poured-into ice, stirring continuously. and sodium carbonate then added until a concentration oi the same of 10 per cent. is obtained. The solution is extracted several times with ether and then heated for 1 hour to ,C. After cooling, the mixture is acidified with hydrochloric acid and the flocculent sol'l-monopropionate, also cooled to 10 C. The 00 or the primary methylismmtml' monosuli'ate completely precipitated by the addition oi common salt. I

In a similar way, the monophosphates derived from diethyl-stilboestrol or similar polyhydroxy compounds of the stilbene or diphe nylhexane series or their salts are obtained. 4

What we claim is: 1. a steroid ester of mi rot-mm wherein R standsfor ia radical containing a cyclopentanopclyhydrophenanthrene nucleus with hydrochloric acid and worked up as debearing the substituentxinone'oi'the positims phosphoric acid ester group being in one of the positions 3 and 1'1.

3. A phosphoric acid ester of androstenediol, the, phosphoric acid ester group being in one of the positions 3 and 17.

4. The 3-vmonophosphate of androstenediol.

5 5. The 3-monophosphate of estradiol.

6. The l'l-monophosphate of estradiol.

KARL MIESCHER. CHARLES MEYSTRE. 

